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Are RNA fragments making gene tweaks in descendants?

By Andy Coghlan

IT HAS always been mysterious. How can the effects of things we experience in our lifetimes be passed on to our children without any changes to the genetic code? The answer could lie in tiny fragments of RNA that are passed on in sperm cells.

Now Isabelle Mansuy of the University of Zurich in Switzerland and her colleagues have identified a mechanism in mice that sidesteps the usual objections. The team’s work suggests that the process relies on tiny fragments of RNA in sperm.

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The specific microRNAs (miRNAs) identified are ones initially produced in response to stress or long-standing lifestyle factors such as famine, overeating or lack of exercise.

Mansuy’s team looked at the sperm of adult mice that had gone through significant stress – being separated from their mothers at birth. There they found an excess of the miRNA molecules.

Behaviourally, the stressed mice were more daring yet more despairing than normal mice. For instance, they took just half the time of normal mice to venture into new avenues and well-lit spaces, yet gave up far sooner in a swimming endurance test.

Mansuy found the same unusual molecules in the sperm of pups and grandpups of the stressed mice, and found broadly the same behaviours too (Nature Neuroscience, doi.org/r9z).

“Studies of this sort highlight the idea that temporary experiences in one generation could influence the behaviour of future generations that were never exposed to the same experience,” says Moshe Szyf of McGill University in Montreal, Canada. “If this is true in humans, it has immense moral, social and political implications.”

But how exactly do they get passed on? When produced in excess during times of adversity, these particular miRNAs trigger epigenetic changes, which alter gene activity to cope with these environmental hardships.

However, there are processes that should undo these changes before genes are passed to the next generation – for example, changes are purged during the formation of sperm and egg and during development. But even though the changes are no longer in the sperm’s genes in this case, the miRNAs remain in the cytoplasm of sperm cells. They get passed into the egg during fertilisation, and as the embryo grows in the womb, the miRNAs get to work, reinstating the same epigenetic changes in the embryo that were in its father.

Most research on epigenetics has focused on the way everyday experiences alter patterns of gene activity in DNA during life through a chemical process of gene tagging called methylation, which usually silences genes. But geneticists remained doubtful that these changes can be passed down because of how inheritable DNA is cleared of changes.

The way the miRNA sidesteps these objections is underlined in Mansuy’s most dramatic experiment. Her team took purified extracts of the miRNA from stressed mice and injected them into normal embryos.

When born, the injected mice had the same abnormal behaviour as the stressed mice, whereas those injected with control RNA didn’t, coming close to proving that the miRNAs were transmitting the abnormal behaviour. Mansuy suspects the process operates down the female line too, because immature female eggs also contain miRNAs, although she hasn’t investigated this yet. This could explain how epigenetic changes were passed to the children of women who were starving during pregnancy.

Mansuy says there is no reason to doubt that the same processes occur in humans.

“I think it’s very strong and novel evidence for a mechanism involved in the transmission of lifestyle experience,” she says. “It shows how environmental factors can alter the genome without changing the sequences of genes, but by altering how the genome is regulated.”

It shows how factors can alter the genome without changing the sequences of genes

Szyf says Mansuy’s mechanism is a completely plausible way for environmental effects to get passed down to the next generation through sperm. “Small RNA in sperm might well be a sensor that registers paternal experience and transfers it to the offspring,” he says.